DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Long-term exposure - systemic effects

Dermal

In a 90-day oral toxicity study performed in rats with fatty acids, C18-unsaturated, dimers, the NOAEL for systemic toxicity was 741 and 855 mg/kg bw/day for males and females, respectively. Based on sensitivity, the NOAEL value for male rats was selected as relevant dose descriptor.

For the dermal exposure route, the dose descriptor is converted into a corrected starting point by route-to route extrapolation.

Due to their physicochemical properties, the skin penetration potential of dimeric and trimeric fatty acids is expected to be very low. Penetration of the stratum corneum is facilitated by high lipophilicity, but because of the low solubility in water, transfer into the epidermis and hence dermal uptake is likely to be low. Due to variations in the grade of saturation and type of dimeric/trimeric structure, the molecular weight of fatty acids, C18-unsaturated, dimers is not restricted to a single value. However, the molecular weight of a C36 fatty acid is estimated to be around 500 g/mol and above, hence too large for being dermally absorbed.

Taking this information into account, along with the weight of evidence that monomeric C16 and C18 fatty acids are negligibly absorbed through human (in vitro) and rat skin (in vitro and in vivo) (Howes, 1975), the absorption of fatty acids, C18-unsaturated, dimers through human skin in vivo is considered to be not significant. In terms of the assessment of systemic long-term effects upon dermal exposure, a dermal absorption of 1% of the oral absorption was assumed as a worst case scenario. Thus, a modification factor of 0.01 was applied for correction of differences between dermal and oral absorption, yielding a dermal NAEL of 74100 mg/kg bw/day.

The DNEL for long-term effects is derived by applying an assessment factor (AF) for allometric scaling of 4, an interspecies AF of 2.5, an intraspecies (human) AF of 5 for worker, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 100. Applying this total AF to the dermal NAEL mentioned above, results in a DNEL for dermal long-term effects of 741 mg/kg bw/day. Taking into account the modification factor for differences between oral and dermal absorption, the overall AF is 1 (0.01 x 100).

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 741 mg/kg bw/day

Step 2) Modification of starting point

Correction for differences between dermal and oral absorption

0.01

Step 3) Assessment factors

InterspeciesIntraspeciesExposure durationQuality of data base

4 x 2.5521

DNEL value

741 mg/kg bw/day(741/[0.01 x 4 x 2.5 x 5 x 2 x 1])

Inhalation

For the inhalative exposure route, the dose descriptor mentioned above (NOAEL = 741 mg/kg bw/day) should be converted into a corrected starting point by route-to route extrapolation.

The dose descriptor is converted into an inhalatory NAEC (in mg/m³) first by using an 8 h standard respiratory volume of 0.38 m³/kg bw for the rat. Additionally, differences between oral and inhalative absorption should be taken into account. Based on physicochemical properties and toxicokinetic information, absorption through epithelial barriers is generally expected to be low. In view of the fact that for (dietary) fatty acids of lower molecular weight oral absorption is facilitated by fluids present in the gastrointestinal but not in the respiratory tract, absorption through the lung epithelium is not expected to be higher than through the intestinal epithelium. Therefore, for the oral-to-inhalation extrapolation, a factor of 1 (no difference in absorption) is included and considered to sufficiently account for differences in oral and inhalative absorption. Finally, a further modification factor of 0.67 is applied to account for differences in 8 h inhalative volumes between workers in rest (6.7 m³) and workers under light activity (10 m³). This results in an inhalatory NAEC of 1306.5 mg/m³/day.

The DNEL for long-term exposure is derived by applying an assessment factor (AF) for remaining interspecies differences of 2.5, an intraspecies (human) AF of 5 for worker, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 25. Applying this total AF to the inhalatory NAEC mentioned above, results in an inhalation DNEL for systemic effects after long-term exposure of 52.26 mg/m³.

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

Step 1) Relevant dosedescriptor

NOAEL(oral, rat) = 741 mg/kg bw/day

Step 2) Modification of starting point

Conversion into inhalatory NAEC (in mg/m³) by using an 8-h standard respiratory volume for the rat

Correction for differences between dermal and oral absorption

Correction for differences in 8-h inhalative volumes between workers in rest and workers under light activity

0.38 m³/kg bw

1

6.7 m³/10 m³

Step 3) Assessment factors

InterspeciesIntraspeciesExposure durationQuality of data base

2.5521

DNEL value

52.26 mg/m³(741 x [1/0.38] x 1 x [6.7/10] x [1/(2.5 x 5 x 2 x 1)])

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.887 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

370.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

2

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.705 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Long-term exposure - systemic effects

Dermal

In a 90-day oral toxicity study performed in rats with fatty acids, C18-unsaturated, dimers, the NOAEL for systemic toxicity was 741 and 855 mg/kg bw/day for males and females, respectively. Based on sensitivity, the NOAEL value for male rats was selected as relevant dose descriptor.

For the dermal exposure route, the dose descriptor is converted into a corrected starting point by route-to route extrapolation.

Due to their physicochemical properties, the skin penetration potential of dimeric and trimeric fatty acids is expected to be very low. Penetration of the stratum corneum is facilitated by high lipophilicity, but because of the low solubility in water, transfer into the epidermis and hence dermal uptake is likely to be low. Due to variations in the grade of saturation and type of dimeric/trimeric structure, the molecular weight of fatty acids, C18-unsaturated, dimers is not restricted to a single value. However, the molecular weight of a C36 fatty acid is estimated to be around 500 g/mol and above, hence too large for being dermally absorbed.

Taking this information into account, along with the weight of evidence that monomeric C16 and C18 fatty acids are negligibly absorbed through human (in vitro) and rat skin (in vitro and in vivo) (Howes, 1975), the absorption of fatty acids, C18-unsaturated, dimers through human skin in vivo is considered to be not significant. In terms of the assessment of systemic long-term effects upon dermal exposure, a dermal absorption of 1% of the oral absorption was assumed as a worst case scenario. Thus, a modification factor of 0.01 was applied for correction of differences between dermal and oral absorption, yielding a dermal NAEL of 74100 mg/kg bw/day.

The DNEL for long-term effects is derived by applying an assessment factor (AF) for allometric scaling of 4, an interspecies AF of 2.5, an intraspecies (human) AF of 10 for the general population, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 200. Applying this total AF to the dermal NAEL mentioned above, results in a DNEL for dermal long-term effects of 370.5 mg/kg bw/day. Taking into account the modification factor for differences between oral and dermal absorption, the overall AF is 2 (0.01 x 200).

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 741 mg/kg bw/day

Step 2) Modification of starting point

Correction for differences between dermal and oral absorption

0.01

Step 3) Assessment factors

InterspeciesIntraspeciesExposure durationQuality of data base

4 x 2.51021

DNEL value

370.5 mg/kg bw/day(741/[0.01 x 4 x 2.5 x 10 x 2 x 1])

Inhalation

For the inhalative exposure route, the dose descriptor mentioned above (NOAEL = 741 mg/kg bw/day) should be converted into a corrected starting point by route-to route extrapolation.

The dose descriptor is converted into an inhalatory NAEC (in mg/m³) first by using a 24 h standard respiratory volume of 1.15 m³/kg bw for the rat. Additionally, differences between oral and inhalative absorption should be taken into account. Based on physicochemical properties and toxicokinetic information, absorption through epithelial barriers is generally expected to be low. In view of the fact that for (dietary) fatty acids of lower molecular weight oral absorption is facilitated by fluids present in the gastrointestinal but not in the respiratory tract, absorption through the lung epithelium is not expected to be higher than through the intestinal epithelium. Therefore, for the oral-to-inhalation extrapolation, a factor of 1 (no difference in absorption) is included and considered to sufficiently account for differences in oral and inhalative absorption. This results in an inhalatory NAEC of 644.3 mg/m³/day.

The DNEL for long-term exposure is derived by applying an assessment factor (AF) for remaining interspecies differences of 2.5, an intraspecies (human) AF of 10 for the general population, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 50. Applying this total AF to the inhalatory NAEC mentioned above, results in an inhalation DNEL for systemic effects after long-term exposure of 12.887 mg/m³.

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 741 mg/kg bw/day

Step 2) Modification of starting point

Conversion into inhalatory NAEC (in mg/m³) by using an 8-h standard respiratory volume for the rat

Correction for differences between dermal and oral absorption

1.15 m³/kg bw

1

Step 3) Assessment factors

InterspeciesIntraspeciesExposure durationQuality of data base

2.51021

DNEL value

12.887 mg/m³(741 x [1/1.15] x 1 x [1/(2.5 x 10 x 2 x 1)])

Oral

For the oral exposure route, the same bioavailability for experimental animals and humans is assumed as a worst case. Therefore, no further modifications of the dose descriptor are necessary, corresponding to a modification factor of 1 to account for differences in oral absorption between rats and humans.

The DNEL for long-term effects is derived by applying an assessment factor (AF) for allometric scaling of 4, an interspecies AF of 2.5, an intraspecies (human) AF of 10 for the general population, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 200. Applying this total AF to the oral NOAEL mentioned above, results in a DNEL for oral long-term effects of 3.705 mg/kg bw/day.

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 741 mg/kg bw/day

Step 2) Modification of starting point

Correction for differences in oral absorption between rats and humans

1

Step 3) Assessment factors

InterspeciesIntraspeciesExposure durationQuality of data base

4 x 2.51021

DNEL value

3.705 mg/kg bw/day(741/[1 x 4 x 2.5 x 10 x 2 x 1])

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